Preparative scale synthesis of the biaryl core of anacetrapib via a ruthenium-catalyzed direct arylation reaction: Unexpected effect of solvent impurity on the arylation reaction

Article abstract of DOI:10.1021/jo1018574

In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.(Figure Presented)

Full text of DOI:10.1021/jo1018574

pubs.acs.org/joc
a simple arene (Ar-H), thus minimizing the number of
Preparative Scale Synthesis of the Biaryl Core of
Anacetrapib via a Ruthenium-Catalyzed Direct
Arylation Reaction: Unexpected Effect of Solvent
Impurity on the Arylation Reaction†
functional group manipulations prior to cross-coupling.
Importantly, this strategy not only is advantageous because
of its economical and ecological benefits but also allows for
streamlining organic syntheses. In this context, the use of
direct arylation represents an interesting option for the large
scale preparation of active pharmaceutical ingredients such
as Anacetrapib (1), a compound currently in development at
Merck for the treatment of hypercholesterolemia.
,‡
Stephane G. Ouellet,* Amelie Roy, Carmela Molinaro,
‡
‡
ꢀ
ꢀ
Remy Angelaud, Jean-Franc-ois Marcoux,
‡
§
ꢀ
Paul D. O’Shea,‡ and Ian W. Davies§
‡Department of Process Research, Merck Frosst Canada,
Kirkland, Quebec, Canada, and Department of Process
Atherosclerosis is the leading cause of illness and death in
North America, Europe, and most developed countries.3 It is
believed that an increase in HDL level (“good cholesterol”)
could result in a decrease in the incidence of arteriosclerotic
vascular disease. One promising new approach targets chole-
steryl ester transfer protein (CETP). This glycoprotein is
involved in the recycling of HDL particles into less desirable
LDL and VLDL.4
§
Research, Merck & Company, Rahway,
New Jersey 07065-4646, United States
stephane_ouellet@merck.com
Received September 20, 2010
Anacetrapib (MK-0859, 1)5 has been identified as a potent
and selective inhibitor of CETP that could provide an
interesting new advance for the prevention and treatment
of hypercholesterolemia.6-8 We were interested in developing
chemistry suitable for the preparation of kilogram quantities
of 1 in an effort to support the exploration of its pharmaco-
logical properties. Our retrosynthetic analysis was centered
around biaryl alcohol 2 that we hoped to prepare via a
ruthenium-catalyzed direct arylation reaction. While we were
actively involved in the optimization of this transformation,
we observed an unprecedented and remarkable effect of a
low-level impurity, γ-butyrolactone, found in the solvent
used for this metal-catalyzed reaction. In the recent litera-
ture, we can find examples in which a beneficial effect of a
low-level contaminant has been reported; however, the im-
purities were often found in the metal catalyst used. This was
In this report, we disclose our findings regarding the remark-
able effect of a low-level impurity found in the solvent used
for a ruthenium-catalyzed direct arylation reaction. This
discovery allowed for the development of a robust and high-
yield arylation protocol that was demonstrated on a multi-
kilogram scale using carboxylate as the cocatalyst. Finally, a
practical, scalable, and chromatography-free synthesis of
the biaryl core of Anacetrapib is described.
(3) Lloyd-Jones, D.; Adams, R.; Carnethon, M.; De Simone, G.;
Ferguson, B.; Flegal, K.; Ford, E.; Furie, K.; Go, A.; Greenlund, K.; Haase,
N.; Hailpern, S.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lackland, D.;
Lisabeth, L.; Marelli, A.; McDermott, M.; Meigs, J.; Mozaffarian, D.;
Nichol, G.; O’Donnell, C.; Roger, V.; Rosamond, W.; Sacco, R.; Sorlie,
P.; Stafford, R.; Steinberger, J.; Thom, T.; Wasserthiel-Smoller, S.; Wong,
N.; Wylie-Rosett, J.; Hong, Y. Circulation 2009, 119, 480.
(4) (a) Zhong, S.; Sharp, D. S.; Grove, J. S.; Bruce, C.; Yano, K.; Curb,
J. D.; Tall, A. R. J. Clin. Invest. 1997, 12, 2917. (b) Bruce, C.; Sharp, D. S.;
Tall, A. R. J. Lipid Res. 1998, 39, 1071.
(5) Vergeer, M.; Kastelein, J. J. P. Nat. Clin. Pract. Cardiovasc. Med.
2008, 5, 302.
(6) Pfizer entered a phase III clinical study with Torcetrapib. This study
was halted in 2006 because of elevated blood pressure. Initial studies revealed
that Anacetrapib could elevate HDL with no effect on blood pressure.
(7) O’Neill, E.; Sparrow, C. P.; Chen, Y.; Eveland, S.; Frantz-Wattley, B.;
Milot, D.; Sinclair, P. J.; Ali, A.; Lu, Z.; Smith, C. J.; Taylor, G.; Thompson,
C. F.; Anderson, M. S.; Cumiskey, A.; Rosa, R.; Strain, J.; Peterson, L. B. J.
Clin. Lipidol. 2007, 1, 367.
Transition metal catalysis has contributed significantly to
the synthesis of biaryl molecules. The most common meth-
ods involve the use of palladium catalysts and require activa-
tion of both coupling partners.1 Recently, direct arylation
has emerged as an increasingly viable alternative to tradi-
tional cross-coupling reactions.2 In these transformations,
the organometallic cross-coupling partner is substituted with
(8) (a) Ali, A.; Napolitano, J. M.; Deng, Q.; Lu, Z.; Sinclair, P. J.; Taylor,
G. E.; Thompson, C. F.; Quraishi, N.; Smith, C. J.; Hunt, J. A.; Dowst, A. A.;
Chen, Y.-H.; Li, H. PCT Int. Appl. WO 2006014413, 2006. (b) Ali, A.;
Napolitano, J. M.; Deng, Q.; Lu, Z.; Sinclair, P. J.; Taylor, G. E.; Thompson,
C. F.; Quraishi, N.; Smith, C. J.; Hunt, J. A. PCT Int. Appl. WO 2006014357,
2007. (c) Ali, A.; Sinclair, P. J. PCT Int. Appl. WO 2007041494, 2007. (d) Ali,
A.; Sinclair, P. J.; Taylor, G. E. PCT Int. Appl. WO 2007081570, 2007.
(e) Ali, A.; Lu, Z.; Sinclair, P. J.; Chen, Y.-H.; Smith, C. J.; Li, H. PCT Int.
Appl. WO 2007079186, 2007.
(9) For examples of Ni-contaminated Cr(II)-catalyzed coupling reac-
tions, see: (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto,
K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (b) Jin, H.; Uenishi, J.-I.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
† Dedicated to the memory of late Professor Keith Fagnou (1971-2009).
(1) For general references on Pd-catalyzed cross-coupling reactions, see:
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Meijere, A. d.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(2) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (b) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(c) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 24, 4087. (d) Chen, X.;
Engle, K.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(e) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
(f) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (g) Li, B.-J.; Yang, S.-D.;
Shi, Z.-J. Synlett 2008, 949. (h) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev.
2007, 36, 1058.
1436 J. Org. Chem. 2011, 76, 1436–1439
Published on Web 02/01/2011
DOI: 10.1021/jo1018574
r
2011 American Chemical Society

Ouellet et al.
JOCNote
TABLE 1. SNAr Reaction between 5 and Potassium Methoxide
entry MeOK (equiv) time (h) bis-OMe (%) yield of 6a (%) 6:7 ratio
1
2
1.2
5.0
4
18
<0.7
9
92b
88
18:1
65:1
aAssay yield measured by HPLC analysis. bThe isolated yield after
distillation was 90%.
FIGURE 1. Retrosynthetic analysis of Anacetrapib (1).
the case for the Cr(II)-catalyzed cross-coupling reaction
reported by Kishi9 and for the Fe-promoted coupling reaction
described by Buchwald and Bolm.10 Herein, we disclose how
our findings with regard to the remarkable effect of the
γ-butyrolactone impurity on the ruthenium-catalyzed direct
arylation reaction allowed the development of a practical
and chromatography-free synthesis of the biaryl core of 1 on
a multikilogram scale.11
SCHEME 1. Preparation of Aryl Bromide 3
Biaryl alcohol 2 is a key intermediate in the preparation of
Anacetrapib (1) as we envisioned a late stage displacement
of its chloride by the corresponding oxazolidinone.12 This
building block would be obtained from a ruthenium-catalyzed
direct arylation reaction between bromoanisole 3 and 2-aryl-
oxazoline 4 (Figure 1). Both coupling partners would be
prepared from readily available starting materials.
SCHEME 2. Preparation of Oxazoline 4
In the development of this synthetic sequence, significant
consideration was placed on the selection of an appropriate
approach to addressing the preparation of the biaryl core.
While several traditional cross-coupling reactions were possible,
the use of a directed arylation strategy appeared to be far
more interesting. For the development of large scale synthesis of
intermediates with commercialization potential, the oppor-
tunity to avoid functional group manipulation and/or acti-
vation steps is highly desirable. The cost associated with the
various transformations and the bulk availability of the
starting materials and the reagents used were also important
discriminating factors in the selection of the synthetic path.
The synthetic efforts began with the preparation of 4-iso-
propyl-2-bromo-5-fluoroanisole (3). To access this intermedi-
ate, 1-bromo-2,4-difluorobenzene (5) was identified as being
the starting material of choice. This building block is readily
available in bulk quantity and is relatively inexpensive. From
this starting material, a selective and high-yield SNAr reaction
between 5 and potassium methoxide was developed.13
A significant improvement in selectivity was observed as
the amount of methoxide used increased (Table 1). The im-
proved selectivity arises from the favored consumption of the
undesired isomer (7) that reacts faster in a second methoxide
addition than the desired isomer (6).14 This transformation
provided access to 2-bromo-5-fluoroanisole in a 90% iso-
lated yield in a 18:1 ratio.15
To introduce the isopropyl side chain, we developed a
three-step sequence (Scheme 1). The acyl moiety was intro-
duced via a Friedel-Crafts acylation of 6 in the presence of
acetyl chloride and aluminum trichloride.16 The acetophe-
none 8 was isolated in 96% yield as a white solid, and all the
isomeric side products generated in the previous step were
rejected during the crystallization [99.3 LCAP (liquid chro-
matography area percent)]. The carbinol 9 was obtained by
addition of 8 to a cold solution of methylmagnesium chloride
in THF. Under these conditions, a high level of conversion
(99.8%) was achieved that obviated the use of an additive
such as cerium trichloride. Following a cold hexane swish,
the carbinol 9 was obtained in 94% yield as a white solid.
Finally, the tertiary alcohol was reduced using tetramethyl-
disiloxane and TFA. Three low-level impurities were typically
observed: the corresponding styrene and two isomeric dimers
presumably formed via a carbocation intermediate. The
formation of those impurities could be minimized by care-
fully keeping the reaction temperature below -5 °C. The
dimers were easily rejected by distillation (from 0.7 to <0.1
LCAP) as well as most of the siloxane byproduct. Finally, the
oxazoline 4 was obtained from the calcium chloride-catalyzed
condensation of 3-(trifluoromethyl)benzonitrile 10 and etha-
nolamine in xylene (Scheme 3).
(10) For examples of copper-contaminated Fe-catalyzed cross-coupling
reactions, see: Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586.
(11) Angelaud, R.; O’Shea, P.; Ouellet, S.; Roy, A. PCT Int. Appl. WO
2007136672, 2007.
(12) For the preparation of the oxazolidinone, see: Miller, R. A. PCT Int.
Appl. WO 2008/082567, 2008.
(13) Ouellet, S. G.; Bernardi, A.; Angelaud, R.; O’Shea, P. D. Tetrahe-
dron Lett. 2009, 50, 3776.
(14) The bis-addition product formed could easily be removed by frac-
tional distillation to provide a highly enriched mixture of isomer 6.
(15) After fractional distillation (90 °C, 3-5 Torr), the isomeric ratio was
18.5:1 (6:7) with 0.48% 1-bromo-2,4-dimethoxybenzene. These impurities
were rejected during the crystallization of acylated product 8.
With both coupling partners in hand, we set out to identify
the optimal reaction conditions to access the biaryl core of
Anacetrapib. Our efforts were initially inspired by an article
reported by Oi, Inoue, and co-workers in which an efficient
ruthenium-catalyzed cross-coupling reaction between oxazolines
(16) Other Lewis acids such as BiCl3, Bi(OTf)3, TFAA/H3PO4, and TiCl4
were tried without success.
J. Org. Chem. Vol. 76, No. 5, 2011 1437

Ouellet et al.
JOCNote
and aryl bromide was described.17 Initially, the reaction
of bromoanisole 3 and oxazoline 4 was examined using
2.5 mol % [RuCl2(μ6-C6H6)]2 and 10 mol % PPh3 in the
presence of 2 equiv of K3PO4 in NMP at 120 °C for 20 h.
Under these conditions, we were pleased to observe good
conversion and a generally clean reaction profile. We next set
out to evaluate each of the reaction parameters independently
to identify the optimal reaction conditions. We first tested
several ligands to determine that electron rich [such as (Cy)3P],
electron deficient [such as (4F-C6H4)3P], or bidentate (such
as dppf) ligands typically provided the coupled adduct in
lower yields. The use of [RuCl2(p-cymene)]2 was also eval-
uated but offered no significant advantages in terms of cost
or reaction efficiency. While K2CO3 and Cs2CO3 were also
found to be acceptable bases, the use of organic bases such as
i-Pr2NEt or Et3N failed to afford 10 in good yields. Finally,
polar aprotic solvents such as NMP, DMA, and DMF18
were found to be suitable for this transformation, while a less
polar solvent such as toluene or xylene afforded the desired
product in lower yields.
TABLE 2. Optimization of the Ru-Catalyzed Direct Arylation
Reaction between 3 and 4
entry
solvent (lot)a
additive
conversion (%)b
1
2
3
NMP (lot A)
NMP (lot B)
NMP (lot B)
-
-
>98
30-50
>98c
4
5
NMP (lot A)
NMP (lot B)
AcOKd
AcOKd
>98
>98
aNMP (lot A): contained 0.3-0.6% butyrolactone, detected by 1H
NMR. NMP (lot B): butyrolactone not detected by 1H NMR. bConver-
sion measured by HPLC analysis. Reactions were repeated at least
twice on a 5-20 g scale. cButyrolactone (0.5 vol %) was added. dAcOK
(10 mol %) was added.
In the development of this catalytic process, it was very
important to identify the best balance between reproducibility
(or robustness) and low catalyst loading. While the optimized
reaction conditions were highly reproducible at a higher
catalyst loading (5 mol % Ru), we observed significant
variability (30-99% conversion) when the catalyst loading
was reduced to 0.5-1 mol % Ru. This variability was even
more pronounced when we conducted this transformation
on a multigram scale. We first suspected the agitation mode
to be responsible for this notable lack of reproducibility, but
side-by-side experiments in which mechanical and magnetic
stirring were compared provided comparable results.19 This
was also consistent with the fact that the particle size of the
K3PO4 used had a negligible impact on the reaction outcome.
We observed a small effect associated with the heating rate
and the order of addition of the various reagents. We typi-
cally observed a slightly higher level of conversion when a
solution of the catalyst and ligand was added to a warm
reaction mixture. This alone, however, did not explain the
large variability that was observed. We noted the most signif-
icant variations in reaction efficiency when different lots of
NMP were tested (the level of conversion would vary between
30 and 99%).
A careful examination of the different lots of solvent
revealed the presence of a low-level impurity that was identi-
fied as being γ-butyrolactone.20 We observed that the effi-
ciency and reproducibility of the cross-coupling reaction were
enhanced in the presence of an appreciable amount of
γ-butyrolactone [complete conversion of the starting materials
(Table 2, entry 1)]. On the other hand, reactions involving
γ-butyrolactone-free NMP proceeded poorly (entry 2). This
was confirmed with a control experiment in which γ-butyro-
lactone was added to a reaction mixture that previously
failed (using lot B). In this case, we were able to fully restore
the catalyst activity and observe a high level of conversion
(entry 3). To address this reproducibility issue, we hypothe-
sized that in the presence of K3PO4 and a trace amount of
water, a certain concentration of carboxylate resulting from
the hydrolysis of γ-butyrolactone could have been formed
and acted as a soluble carboxylate source that enhanced the
reactivity and/or stability of the ruthenium catalyst. In line
with these observations, it was shown that highly efficient
and reproducible reactions could be realized when a catalytic
amount of potassium acetate was added to the reaction
mixture (entries 4 and 5).21,23
Interestingly, most of the Ru-catalyzed direct arylation
reactions reported use NMP as the optimal solvent.22 In some
cases, remarkable differences in reactivity were noted between
NMP and other solvents that share very similar properties
(such as DMF and DMA).23 It is possible that the improved
reaction profiles observed in NMP are in fact due to the
presence of trace amounts of γ-butyrolactone that is known
to be a common impurity found in NMP. Our hypothesis is
further supported by recent publications describing the bene-
ficial effect of carboxylate additives in direct arylation reac-
tions. While this strategy was first developed in the context
of palladium-catalyzed direct arylation reactions,24 recent
publications demonstrate its application in ruthenium-cata-
lyzed reactions.25 Moreover, recent reports by Ackermann
described the utilization of carboxylic acid additives as co-
catalysts to enhance the ruthenium-catalyzed arylation reaction
(21) Other additives such as TFA, pivalic acid, and 4-methylbenzoic acid
were tested and were found to have a favorable effect on the reaction
efficiency.
(22) Forarecentreviewonmetal-catalyzeddirectarylation, see: Ackermann,
L.; Vivente, R. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH:
Weinheim, Germany, 2009; pp 311-399. For selected examples of reactions
€
developed in NMP, see: (a) Ozdemir, I.; Demir, S.; C-etinkaya, B.; Gourlaouen,
C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156.
(b) Ackermann, L. Org. Lett. 2005, 7, 2123. (c) Oi, S.; Sakai, K.; Inoue, Y. Org.
Lett. 2005, 7, 4009.
ꢀ
(23) (a) Ackermann, L.; Novak, P.; Vivente, R.; Hofmann, N. Angew.
Chem., Int. Ed. 2009, 48, 6045. (b) Ackermann, L.; Althammer, A.; Born, R.
Angew. Chem., Int. Ed. 2006, 45, 2619.
(24) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
14570. (c) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326.
(d) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem.
Soc. 2003, 125, 11506.
(25) (a) Arockiam, P.; Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf,
ꢁ
P. H. Green Chem. 2009, 11, 1871. (b) Pozgan, F.; Dixneuf, P. H. Adv. Synth.
Catal. 2009, 351, 1737. (c) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10,
(17) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113.
(18) On a 1 mmol scale, >90% conversion was observed, and the reaction
profile was slightly cleaner when NMP was used.
(19) These studies were conducted on a 5-10 g scale.
(20) γ-Butyrolactone is a common impurity found in NMP.
5043.
1438 J. Org. Chem. Vol. 76, No. 5, 2011

Ouellet et al.
JOCNote
SCHEME 3. Preparation of the Biaryl Core of Anacetrapib
consider the use of a carboxylate additive that allowed the
reduction of catalyst loading while maintaining reproducibly
high yields. This transformation was the key step in the efficient,
practical, high-yield (65% overall yield), and chromatography-
free seven-step synthesis of the biaryl precursor of Anace-
trapib. To the best of our knowledge, this is the first example
of a ruthenium-catalyzed direct arylation reaction to be
successfully demonstrated on a multikilogram scale.
Experimental Section
Procedure Developed for the Kilogram Scale Ruthenium-
Catalyzed Direct Arylation Reaction. A visually clean and dry
50 L reactor equipped with an overhead stirrer, a reflux con-
denser, a nitrogen inlet, and a temperature probe was charged
with oxazoline 3 (2755.5 g) followed by anisole 4 (3065.7 g) and
NMP (10 L predegassed with bubbling nitrogen for 60 min). The
reaction mixture was degassed by bubbling nitrogen for 30 min, and
then K3PO4 (4842.1 g) and KOAc (112.5 g) were charged
followed by 2 L of degassed NMP (rinse). This suspension was
degassed for an additional 60 min. The reaction mixture was
then heated to 130 °C. A 5 L reactor was charged with degassed
NMP (2 L) and triphenyl phosphine (29.92 g) and then degassed
with bubbling nitrogen for 30 min at rt. The benzeneruthenium(II)
chloride dimer complex (28.5 g) was then added, and this solution
was degassed for an additional 30 min at room temperature.
When the reaction mixture reached 130 °C, half of the ruthe-
nium solution (1 L) was transferred, the reaction temperature
was lowered to 110 °C, and the mixture was stirred at this
temperature for 2 h before the addition of the second half of the
ruthenium catalyst. Then, the reaction mixture was stirred at
this temperature for an additional 7 h before being cooled to
room temperature. To isolate the product, water (17 L) was
added slowly (over 2.5 h) while the temperature was kept below
25 °C (at this point, an HPLC assay of the supernatant showed
1.6 g/L of product). The resulting slurry was then filtered
through a filter pot, and the reaction flask was rinsed. The
resulting solid was rinsed with an NMP/water mixture (1:1.5,
15 L), followed by water (40 L), and dried under a flow of nitrogen.
Biaryl oxazoline 11 was obtained as a dark brown solid (4442.1
g, 93 wt %, 96% yield): 1H NMR (500 MHz, CDCl3) δ 7.86 (s,
1H), 7.59 (d, 1H, J=8.0 Hz), 7.30 (d, 1H, J=7.9 Hz), 6.99 (d, 1H,
J=8.6 Hz), 6.68 (d, 1H, J=12.0 Hz), 4.49 (br, 2H), 3.73 (s, 3H),
3.21 (sept, 1H, J = 6.9 Hz), 1.95 (t, 1H, J=6.2 Hz), 1.24 (d, 6H,
J=6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 161.8, 159.9, 155.0
(d, J=10.0 Hz), 140.5, 140.3, 130.9, 130.0 (q, J=32.4 Hz), 129.1
(d, J=7.2 Hz), 127.4, 127.3, 124.5 (q, J=3.7 Hz), 124.2 (q, J=
272.1 Hz), 124.0 (d, J=3.7 Hz), 123.8 (d, J=3.4 Hz), 99.4 (d,
J=27.6 Hz), 62.7, 55.9, 26.6, 22.7; IR (neat) 2968, 1332, 1163,
1153, 1116, 1081, 1035, 831 cm-1; HRMS (ESI) exact mass calcd
for [M þ Na]þ (C18H18F4NaO2) m/z 365.1135, found m/z
365.1141.
between several arenes and aryl halides. Under those condi-
tions, the direct arylation reactions were found to be efficient
in apolar solvent such as toluene26 and polyethylene glycol.27
More recently, the same author reported some mecha-
nistic insight into the direct arylation reaction which led to
the development of well-defined ruthenium(II) carboxylate
catalysts.28
Using our robust catalyst system, the ruthenium-catalyzed
direct arylation reaction was performed on 2.7 kg of 4 and
3.0 kg of 3 to yield 4.4 kg of biaryl 10 with an assay yield of
96% using only 1 mol % catalyst (Scheme 2). To the best of
our knowledge, this is the first report describing a ruthenium-
catalyzed direct arylation reaction to be successfully demon-
strated on a multikilogram scale.29
To complete the synthesis of 2, we developed a practical
method to access the desired alcohol in one pot. Oxazoline 11
could be easily converted to the corresponding N-acylcarba-
mate 12 upon treatment with methyl chloroformate. Sodium
borohydride reduction of the in situ-generated intermediate
12 afforded the desired alcohol 2 in good yield.30 From 2,
Anacetrapib could easily be obtained using chemistry pre-
viously described.31
In summary, we observed a significant difference in the
reaction efficiency and robustness of the ruthenium-catalyzed
direct arylation reactions, which was attributed to the pres-
ence of γ-butyrolactone in NMP. This observation led us to
(26) (a) Ackermann, L.; Vivente, R.; Althammer, A. Org. Lett. 2008, 10,
ꢀ
2299. (b) Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966.
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(27) (a) Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi,
H. K. Synthesis 2010, 2245. (b) Ackermann, L.; Vicente, R. Org. Lett. 2009,
11, 4922.
(28) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org.
Lett. 2010, 12, 5032.
Acknowledgment. We thank Ravi Sharma, Claude Briand,
Dean Hutchings, and Wayne Mullett for analytical support
and Louis-Charles Campeau for helpful discussions during
the preparation of the manuscript.
(29) (a) Jensen, M. S.; Hoerrner, R. S.; Li, W.; Nelson, P. D.; Javadi, G. J.;
Dormer, P. G.; Cai, D.; Larsen, R. D. J. Org. Chem. 2005, 70, 6034.
(b) Gauthier, D. J., Jr.; Limanto, J.; Devine, P. N.; Desmond, R. A.;
Szumigala, R. H., Jr.; Foster, B. S.; Volante, R. P. J. Org. Chem. 2005, 70,
5938. (c) Cameron, M.; Foster, S. B.; Lynch, J. L.; Shi, Y.-J.; Dolling, U.-H.
Org. Process Res. Dev. 2006, 10, 398.
(30) Bernardi, A.; Ouellet, S. G.; Angelaud, R.; O’Shea, P. D. Tetrahe-
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(31) For completion of the synthesis of Anacetrapib, see: Miller, R. A.;
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Supporting Information Available: Procedures, compound
characterization data, and copies of spectra supporting struc-
tural assignments. This material is available free of charge via
the Internet at http://pubs.acs.org.
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